Progress in developing a treatment for Alzheimer's disease (AD) remains minimal, despite the disease affecting one in eight persons over 65 at a burden to the US economy of over $200 billion per year. A significant factor is the lack of effective methods for AD diagnosis and for quantifying the efficacy of investigational new drugs. Despite exciting progress with PET probes in imaging amyloid fibrils found in plaques, which have provided an important focus for AD studies over many years, plaques do not correlate well with cognitive loss, do not offer a timely indicator of disease onset, and are no longer regarded as the initial cause of AD neuron damage. This project addresses the need for a probe that targets molecules that appear earlier in AD pathology and that are responsible for initiating neuron damage. Our choice of target is the toxic A? oligomer (A?O), for which we have prepared a novel molecular MRI probe. Toxic A?Os are regarded by many researchers as instigating the initial stages of AD neuron damage. Evidence indicates A?Os begin to accumulate in early AD, perhaps the first indicator of AD pathology. Our immediate goal is to obtain proof of concept with the 5XFAD tg mouse that our MRI probe (NU4MNS) will track A?Os in vivo as predicted. NU4MNS comprises aqueous-stable magnetic nanostructures (MNS), which act as powerful MRI contrast agents that have been conjugated to our team's NU4 monoclonal antibody. The NU4 parent antibody selectively targets A?Os with high affinity and, when delivered intranasally, it readily targets hippocampal A?Os in a mouse AD model. The NU4MNS probe has shown outstanding potential for MRI diagnostics in preliminary studies. The probe retains full ability to selectively bind A?Os, and it can distinguish in vitro human AD brain samples from controls by MRI signal. The project will undertake three studies to extend our successful initial findings and advance the probe toward our long-range clinical goal of imaging A?Os in AD patients by MRI. (Study 1) Carry out prototype assays for A?O-dependent MRI signals using brain sections from the 5X FAD mouse model. (Study 2) Optimize intranasal delivery of probe to brain of AD and control mice. (Study 3) Obtain proof of concept that mice with AD pathology can be identified using the NU4MNS MRI probe, and that the probe can determine drug efficacy in lowering A?Os in treated animals. Our imaging goal builds on landmark breakthroughs from other teams that have made it possible to clinically image amyloid plaques in Alzheimer's patients. This project is expected to advance imaging resources by developing a new probe can detect neuron- damaging A?Os at early stages of mouse pathology and monitor toxin reduction by an experimental drug. Development of targetable nanostructures specific for neurotoxic A?Os has potential to provide an MR imaging modality for evaluating the disease-modifying efficacy of investigational new drugs (INDs) and ultimately deliver early-stage AD diagnosis and subsequent disease management.